PROJECT SUMMARY ABSTRACT Increased dietary salt intake is strongly correlated with cardiovascular disease and is regarded as a major contributing factor to the pathogenesis of hypertension. Recent time-controlled studies in both humans and rodents suggest a high salt diet elevates cerebrospinal fluid (CSF) [Na+] to elevate SNA and ABP via brain Na+-sensors. The predominant set of brain Na+-sensors is located in the organum vasculosum of the lamina terminalis (OVLT). Interestingly, intracerebroventicular infusion of the epithelial sodium channel (ENaC) antagonist benzamil attenuates osmotically-induced vasopression secretion and the development of salt- sensitive hypertension. I hypothesize that excess dietary salt intake increases CSF [Na+] to activate Na+- sensing OVLT neurons via epithelial sodium channels (ENaC). Subsequent activation of descending pathways through the hypothalamic paraventricular nucleus increase SNA and ABP. This hypothesis is supported by strong preliminary data and will be pursued through two logical aims. Specific Aim 1 will identify the extent by which ENaC mediates the intrinsic Na+-sensing of OVLT neurons using ENaC?lox/lox and ENaC?lox/lox mice injected with rAAV9-Cre-EGFP into the OVLT to abrogate ENaC function. The intrinsic Na+- sensing of OVLT neurons will be assessed using in vitro patch-clamp electrophysiology. Specific Aim 2 will determine the contribution of ENaC activation in OVLT t o SNA and ABP responses evoked by acute sodium loads and chronic sodium loading in the deoxycorticosterone acetate-salt-sensitive model of hypertension. This fellowship will provide a rigorous training and background in autonomic and cardiovascular physiology. Scientifically, the proposed experiments utilize novel ENaC transgenic mice to identify the cellular mechanism in OVLT neurons that detects changes in [Na+] and to determine how this cellular process is altered in salt-sensitive hypertension. Consequently, this proposal will provide a framework to develop therapies that underlie Na+-sensing and its contribution to the pathogenesis of salt-sensitive hypertension.